The goal of this project is to develop early diagnostic tests for pancreatic cancer. We propose two experimental approaches. One is to improve the utility of the CA19-9 and related tests for pancreatic cancer and other GI cancers by adding to the test a determination of the core protein on which this carbohydrate antigen is detected. This proposal is based upon recent discoveries about the molecular nature of different mucin core proteins that are expressed by different adenocarcinomas, the development of new monoclonal antibodies against these core proteins, and recently obtained knowledge that will enable the development of additional reagents that improve this existing diagnostic test. The second experimental approach is to identify novel proteins that are expressed in the sera and body fluids of patients with premalignant lesions of the pancreas (pancreatic intraepithelial neoplasms - PanIn) by using proteomics techniques. We will employ different highly sensitive and complementary proteomics approaches to identify novel proteins and peptides that appear in serum concomitant with the development of advanced premalignant PanIn lesions. Parallel studies will be performed in newly developed murine systems of PanIn lesions and pancreatic cancer. We will also develop and investigate in vitro cell culture model systems (human and mouse) that represent different stages of PanIn lesions. This information will be used to develop tests (conventional serum or body fluid assays or specialized proteomics assays) that can be widely applied to identify individuals with advanced PanIn lesions, who would become candidates for intensive screening programs, chemoprevention studies, and studies of early intervention.